DESCRIPTION: (Applicant's abstract) A number of neurological insults, including seizures, result in excessive release of glutamate and subsequent neuronal injury by a process known as excitotoxicity. Influx of CA2+ through the NMDA subtype of glutamate receptor plays a critical role in excitotoxic injury; the Ca2+-activated signaling pathways underlying excitotoxic injury however, are not clear. Extracellular signal-regulated kinase (ERK) is activated by stimulation of glutamate receptors, influx of Ca2+, and seizures. We have recently fund that PD098059, a selective inhibitor of the upstream activator of ERK, protects hippocampal neurons in a cell-culture model of seizure activity. This result suggests that the ERK pathway plays a role in the seizures or the signaling pathways underlying seizure-induced injury, both novel functions for the ERK pathway. In the proposed studies, the hypothesis that ERK activation is required for seizure-induced neuronal injury will be tested. We will determine the distribution and time- course of ERK activation following kainate-induced seizures and whether intraventricular injections of PD098059 can prevent ERK activation and protect against seizure-induced injury in vivo. The effects of PD098059 on seizure-like events will be assessed in cultured hippocampal neurons using whole-cell patch clamp techniques. We will explore possible pre- and post-synaptic substrates for ERK, synapsin I and the NMDA receptor, that may contribute to seizures and seizure-induced injury. By improving our understanding of the signal transduction pathway underlying seizure-induce injury, this work could lead to the design of novel therapeutic agents that do not unduly interfere with normal brain function.